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The lesions of Parkinson's disease (PD) spread within the central nervous system (CNS) with characteristics of prion diseases. The prion in this case is a misfolded form of alpha-synuclein. We are investigating the mechanism of spread on alpha-synuclein prions with a special attention to axonal transport and transfer of prions between neurons. Understanding these pathways could lead to using drugs to slow down or halt disease progression.

Abstract

The lesions of Parkinson disease spread through the brain in a characteristic pattern that corresponds to axonal projections. Previous observations suggest that misfolded ?-synuclein could behave as a prion, moving from neuron to neuron and causing endogenous ?-synuclein to misfold. Here, we characterized and quantified the axonal transport of ?-synuclein fibrils and showed that fibrils could be transferred from axons to second-order neurons following anterograde transport.We grew primary cortical mouse neurons in microfluidic devices to separate somata from axonal projections in fluidically isolated microenvironments. We used live-cell imaging and immunofluorescence to characterize the transport of fluorescent ?-synuclein fibrils and their transfer to second-order neurons.Fibrillar ?-synuclein was internalized by primary neurons and transported in axons with kinetics consistent with slow component-b of axonal transport (fast axonal transport with saltatory movement). Fibrillar ?-synuclein was readily observed in the cell bodies of second-order neurons following anterograde axonal transport. Axon-to-soma transfer appeared not to require synaptic contacts.These results support the hypothesis that the progression of Parkinson disease can be caused by neuron-to-neuron spread of ?-synuclein aggregates and that the anatomical pattern of progression of lesions between axonally connected areas results from the axonal transport of such aggregates. That the transfer did not appear to be trans-synaptic gives hope that ?-synuclein fibrils could be intercepted by drugs during the extracellular phase of their journey.

Abstract

Discussing the problem of multiple sclerosis and viruses should not be limited to reviewing the epidemiological evidence in favor, or against, a particular candidate, such as Epstein-Barr virus or human herpes virus 6. In this text, I discuss the difficulty of going from association to causation in human epidemiology; the fact that viruses can trigger or prevent autoimmunity; the problem of our very limited knowledge of the viruses that we harbor as part of our metagenome; and the role of such viral flora in multifactorial diseases and also, possibly, in health.

Abstract

We showed previously that Theiler's virus, a neurotropic non-enveloped picornavirus of mouse, traffics from the axon of infected neurons into the surrounding myelin. When this traffic is interrupted, as in the shiverer mouse which bears a mutation in the myelin basic protein gene, the virus is unable to persist in the central nervous system. In the present work, we used the Wld(s) mutant mouse, a strain in which axonal degeneration is considerably slowed down, to show that axon to myelin traffic takes place in the absence of axon degeneration. Our results suggest the existence of a mechanism of transfer of axonal cytoplasm into the myelin which Theiler's virus might exploit to ensure its persistence.